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Case Rep Dermatol 2018;10:46–54 DOI: 10.1159/000487473 Published online: February 21, 2018

© 2018 The Author(s) Published by S. Karger AG, Basel www.karger.com/cde

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Case Series

The Importance of Excluding Cutaneous T-Cell Lymphomas in Patients with a Working Diagnosis of Papuloerythroderma of Ofuji: A Case Series Anthony M. Mahera Ivan V. Litvinov b, c a

Chloé E. Ward b

Steven Glassman b b

Faculty of Medicine, Memorial University, St. John’s, NL, Canada; Division of c Dermatology, University of Ottawa, Ottawa, ON, Canada; Division of Dermatology, McGill University Health Centre, Montreal, QC, Canada

Keywords Cutaneous T-cell lymphomas · Papuloerythroderma of Ofuji · Erythroderma · Mycosis fungoides · Sézary syndrome · Deck-chair sign Abstract Papuloerythroderma of Ofuji (PEO) is an erythroderma-like eruption with flat-topped papules that spare the skin folds (a “deck-chair sign” finding). Many infections, medications, and systemic diseases have been associated with PEO, including cutaneous T-cell lymphomas (CTCL). The relationship between the clinical presentation of PEO and CTCL remains poorly elucidated. Clinical, laboratory, and histopathological data were obtained from the Lymphoma Clinic at the Ottawa Hospital, Canada. We report 5 patients with deck-chair-sign-positive CTCL, mycosis fungoides, and Sézary syndrome variants. We contend that PEO should be viewed as a diagnosis of exclusion and that these patients should be monitored carefully for possible Ivan V. Litvinov, MD, PhD, FRCPC Division of Dermatology, McGill University Health Centre, Room E02.6236 1001 Boulevard Decarie Montreal, QC H4A 3J1 (Canada) E-Mail [email protected]

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Case Rep Dermatol 2018;10:46–54 DOI: 10.1159/000487473

© 2018 The Author(s). Published by S. Karger AG, Basel www.karger.com/cde

Maher et al.: The Importance of Excluding Cutaneous T-Cell Lymphomas in Patients with a Working Diagnosis of Papuloerythroderma of Ofuji: A Case Series

emergence of CTCL. Skin biopsy alone is not sufficient to exclude CTCL in these patients. A skin eruption demonstrating a positive deck-chair sign may signify systemic/leukemic CTCL and, therefore, warrants a thorough investigation, including skin biopsy, flow cytometry, and T-cell receptor clonality studies. © 2018 The Author(s) Published by S. Karger AG, Basel

Introduction

A distinct clinical entity, now known as papuloerythroderma, was first identified by Ofuji et al. in 1984 [1]. Described in 4 male patients in Japan (a human T-cell lymphotropic virus-1 (HTLV-1)-endemic region), this report found an erythroderma-like eruption and flattopped papules that spared the skin folds, a finding later termed the “deck-chair sign” [2]. Peripheral eosinophilia and lymphopenia were also observed in some patients. Unfortunately, the HTLV-1 status in these patients was not reported at that time. With an estimated incidence of 1.5 cases per million individuals per year [3], papuloerythroderma of Ofuji (PEO) remains a rare condition. However, multiple factors indicate that PEO is often underdiagnosed and underreported. Many infections, medications, and, more importantly, systemic diseases have been associated with PEO, including cutaneous T-cell lymphomas (CTCL). The relationship between the clinical presentation of PEO and CTCL remains poorly elucidated. Materials and Methods

The 5 patients reported in this case series provided written informed consent in accordance with the Declaration of Helsinki. Clinical, laboratory, and histopathological data were obtained from the Lymphoma Clinic at the Ottawa Hospital, Canada, and are presented in Table 1 and Figure 1. Case Presentations

Case 1 A 75-year-old Caucasian male was diagnosed with rapidly progressing Sézary syndrome. The initial skin biopsy was diagnostic of CD30+ mycosis fungoides (MF). Notably, during later visits, a re-biopsy of his erythrodermic skin showed nonspecific excoriations, spongiotic changes, and dermal edema with superficial, mixed, acute, and chronic inflammation. Over a period of months, this patient rapidly progressed from 10% body surface area (BSA) patch-plaque disease to 80% BSA involvement, in addition to developing palpable lymph nodes and blood disease with frequent soft-tissue infections. On the physical exam in our clinic, he had classic polygonal, erythematous-brown papules, covering his skin surface and clearly sparing the skin folds (a positive deck-chair sign) (Fig. 1a). Based on recently reviewed diagnostic criteria [4], his laboratory findings confirmed extensive stage IVA1 Sézary syndrome disease and showed lactate dehydrogenase (LDH) 718 U/L (reference range, 100–205 U/L); HTLV-1-negative serology; high Sézary cell count, 85%




T cells on flow leukemia/lymphoma profile, 80% with CD2+, CD3+, CD4+, CD5+, and loss of CD26 and CD7 expression, and a CD4:CD8 ratio of >10 (blood stage B 2 disease); T-cell receptor (TCR) β clonality was confirmed on gene rearrangement analysis by polymerase chain reaction; and bilateral inguinal lymphadenopathy on CT thorax, abdomen, and pelvis. His treatment regimen included topical steroids, topical and systemic antibiotics, isotretinoin, interferon-α, and extracorporeal photophoresis. Later, he developed tumors and acquired large-cell transformation on histology. At that point, extracorporeal photophoresis was discontinued, and the patient was started on brentuximab vedotin. Case 2 A 72-year-old Caucasian female was followed for long-standing stage T1b MF and cutaneous mastocytosis (telangiectasia macularis eruptiva perstans) for over 40 years. Over time, she developed progressive, biopsy-proven, plaque MF, covering 80% of her BSA, but notably sparing her skin folds (Fig. 1b). Further investigations revealed leukemic CTCL. Interestingly, while her leukemic CTCL was diagnosed with flow cytometry and TCR clonality studies, repeat skin biopsy of her erythrodermic skin was not diagnostic and only showed a psoriasiform and spongiotic dermatitis with a lymphocytic inflammatory infiltrate. She was then treated with systemic alitretinoin (as bexarotene is not available in Canada) and interferon-α in addition to skin-directed topical therapies. Laboratory results confirmed stage IVA1 CTCL: LDH 196 U/L; HTLV-1/2 antibodies nonreactive; tryptase 5.3 ng/mL (reference range, 3.8–11.4 ng/mL); 38% circulating Sézary cells, 33% abnormal CD4+ T cells with loss of CD26 and CD7 expression, and T cells comprising 70% of lymphocytes with a CD4:CD8 ratio of 21:1 on flow cytometry leukemia/lymphoma profile (blood stage B2 disease); β, δ, and γ clonality on TCR gene rearrangement; and bilateral, enlarged, inguinal, and axillary lymph nodes on CT thorax, abdomen, and pelvis. Case 3 An 89-year-old male presented with patch lesions affecting ~30% of his BSA, consistent with MF (Fig. 1c). He had a 2-year history of a nonresolving eruption on the trunk that spared the skin folds. Notably, a skin biopsy was not diagnostic of CTCL, and imaging did not reveal any lymphadenopathy or visceral disease. However, flow cytometry analysis documented the presence of Sézary cells, consistent with blood stage B2 disease. Based on these findings, the patient was diagnosed with leukemic CTCL (stage IVA1) and was started on multimodality treatment, including topical steroids, narrow-band ultraviolet B phototherapy, isotretinoin, and interferon-α. Laboratory testing revealed LDH within normal limits and negative HTLV-1 serology. Further investigations demonstrated 44% circulating Sézary cells. Flow cytometry revealed 82% T cells, with 59% of CD4 T cells (44% of lymphocytes) negative for both CD7 and CD26, and a CD4:CD8 ratio of 8.5. β and γ clonality were found on TCR gene rearrangement studies. Case 4 An 82-year-old male with a 5-year history of a pruritic rash that did not respond to topical steroids presented with plaque lesions affecting ~20% of his skin surface with a positive deck-chair sign (Fig. 1d). His MF disease was diagnosed on skin biopsy, and he was found to have a mild blood involvement, based in the TCR β clonality findings in the blood. He did not

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fulfill any other blood involvement criteria, as recently reviewed elsewhere [4]. He was diagnosed with stage IB (T2N0B0b) MF. He received treatment with topical steroids, narrowband ultraviolet B phototherapy, and alitretinoin. LDH was found to be normal, and HTLV-1 status was negative. Imaging studies did not reveal lymph-node or visceral involvement. Case 5 An 86-year-old African-Canadian female native of Guyana had a long-standing indolent T1b plaque MF. Her initial biopsy was diagnostic of CTCL and showed mild acanthosis, keratosis, patchy parakeratosis, spongiosis, moderate epidermotropism, atypical lymphocytes forming Pautrier’s microabscesses, a CD4:CD8 ratio of 6:1, and loss of CD7 expression in the epidermotropic population. Her plaque MF disease had been treated for 6 years with topical steroids. She then developed a positive deck-chair-sign skin eruption (Fig. 1e) and was found to have a leukemic (blood stage B1a) disease with high numbers of CD30+ cells on flow cytometry. Because the patient was mostly asymptomatic, she was treated with alitretinoin and narrow-band ultraviolet B phototherapy. This patient had LDH 207 U/L; HTLV-1/2 antibodies nonreactive; 8% circulating Sézary cells, 49% T cells, 84% CD4+ T cells with loss of CD26 and CD7 expression, CD8+ cells also exhibited a loss of CD7, and co-expression of CD30 in both CD4+ and CD8+ T cells on flow leukemia/lymphoma cytometry profile; no clonality was detected on gene rearrangement studies. Discussion

In a systematic review published in 2010, Torchia et al. [5] proposed diagnostic criteria and etiological classification of papuloerythroderma (summarized in online suppl. Table 1, www.karger.com/doi/10.1159/000487473). Ofuji and others have commented that, while clinically distinct, multiple causative factors including CTCL underlie the development of papuloerythroderma [6]. Two historic case reports are noteworthy for suggesting cutaneous lymphoma as a differential diagnosis of PEO [7, 8]. Since that time, numerous case reports of PEO have supported the diagnosis of CTCL based on histological findings alone [3, 9–14]. The specific diagnosis of folliculotropic MF was made in several cases [10, 12–14]. Notably, a case report of 3 patients from South Korea observed that PEO might be a variant of early MF, leading these authors to recommend a close follow-up for possible emergence of MF/CTCL once PEO is diagnosed [10]. A systematic review further concluded that “papuloerythroderma-like CTCL” [5] is appropriate nomenclature in cases where the histology under consideration is compatible with CTCL. However, it is very important to note that skin biopsy in erythrodermic MF or Sézary syndrome is often not diagnostic [15], and, hence, flow cytometry and TCR rearrangement studies are necessary before a diagnosis of CTCL can be excluded. These combined results and previous studies argue that PEO should be viewed as a diagnosis of exclusion and these patients should be monitored carefully for possible emergence of CTCL. Skin biopsy alone is not sufficient to exclude CTCL in these individuals. A positive deck-chair-sign skin eruption may signify systemic/leukemic CTCL. Therefore, these patients warrant a thorough investigation including flow cytometry and TCR clonality stud-

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ies. Where appropriate, HTLV-1 serology should be ordered in patients originating from HTLV-1-endemic areas, in intravenous drug users, or in individuals at risk of exposures to this virus. We summarize our recommended work-up for these patients in Table 2. Statement of Ethics

All patients provided written informed consent in accordance with the Declaration of Helsinki. Disclosure Statement

The authors declare that they have no competing interests. Funding Sources

This work was supported by the new investigator funding program from the Ottawa Hospital Research Institute to Dr. Litvinov and the Canadian Dermatology Foundation research grants to Dr. Litvinov, Joan Sealy Trust Cancer Research to Dr. Litvinov, and the Fonds de la recherche en santé du Québec (FRSQ) research grant to Dr. Litvinov (No. 34753 and 36769). References 1 2 3 4

5 6 7 8 9 10

Ofuji S, Furukawa F, Miyachi Y, Ohno S: Papuloerythroderma. Dermatologica 1984;169:125–130. Farthing CF, Staughton RC, Harper JI, Rowland Payne CM, Copeman PW: Papuloerythroderma – a further case with the ‘deck chair sign’. Dermatologica 1986;172:65–66. Bech-Thomsen N, Thomsen K: Ofuji’s papuloerythroderma: a study of 17 cases. Clin Exp Dermatol 1998;23:79–83. Olsen EA, Whittaker S, Kim YH, et al: Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011;29:2598–2607. Torchia D, Miteva M, Hu S, Cohen C, Romanelli P: Papuloerythroderma 2009: two new cases and systematic review of the worldwide literature 25 years after its identification by Ofuji et al. Dermatology 2010;220:311–320. Ofuji S: Papuloerythroderma. J Am Acad Dermatol 1990;22:697. Grob JJ, Collet-Villette AM, Horchowski N, Dufaud M, Prin L, Bonerandi JJ: Ofuji papuloerythroderma. Report of a case with T cell skin lymphoma and discussion of the nature of this disease. J Am Acad Dermatol 1989;20:927–931. Wakeel RA, Keefe M, Chapman RS: Papuloerythroderma. Another case of a new disease. Arch Dermatol 1991;127:96–98. Shah M, Reid WA, Layton AM: Cutaneous T-cell lymphoma presenting as papuloerythroderma – a case and review of the literature. Clin Exp Dermatol 1995;20:161–163. Hur J, Seong JY, Choi TS, Jang JG, Jang MS, Suh KS, Kim ST: Mycosis fungoides presenting as Ofuji’s papuloerythroderma. J Eur Acad Dermatol Venereol 2002;16:393–396.

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11 12 13 14 15

Pereiro M Jr, Sanchez-Aguilar D, Pereiro Ferreiros MM, Amrouni B, Toribio J: Cutaneous T-cell lymphoma: an expression of papuloerythroderma of Ofuji. J Eur Acad Dermatol Venereol 2003;17:240– 241. Martinez-Barranca ML, Munoz-Perez MA, Garcia-Morales I, Fernandez-Crehuet JL, Segura J, Camacho F: Ofuji papuloerythroderma evolving to cutaneous T-cell lymphoma. J Eur Acad Dermatol Venereol 2005;19:104–106. Shimauchi T, Ohshima A, Tokura Y: Folliculotropic mycosis fungoides presenting as papuloerythroderma. J Dermatol 2006;33:498–500. Suh KS, Kim HC, Chae YS, Kim ST: Ofuji papuloerythroderma associated with follicular mucinosis in mycosis fungoides. J Dermatol 1998;25:185–189. Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C: Primary cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome): part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol 2014;70:205 e201–e216; quiz 221–222.

Anthony M. Maher and Chloé E. Ward contributed equally to this work.

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Fig. 1. Positive deck-chair-sign (arrows) skin eruption on the trunk of patient 1 (a), who was found to have

Sézary syndrome, and on the trunks of patients 2–5 (b–e), who were diagnosed with mycosis fungoides / cutaneous T-cell lymphoma with evidence of blood involvement.

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Table 1. Patient characteristics in the present case series Case 1

Case 2

Case 3

Case 4

Case 5

Age, years

75

72

89

82

86

Sex

Male

Female

Male

Male

Female

Skin phototype

II

II

II

II

V

Country of origin

Canada

Canada

Canada

Canada

Guyana

Skin involvement

80% BSA, plaque lesions with deck-chair-sign skin findings

80% BSA, patch lesions with deck-chair-sign skin findings

~30% BSA, patch ~20% BSA, plaque lesions with decklesions with deckchair-sign skin findings chair-sign skin findings

75% BSA, plaque lesions with deckchair-sign skin findings

Normal Negative

Normal Negative

Normal Negative

Normal Negative

38% Abnormal T cells with discrete loss of CD26– in 50% of cells CD4:CD8 ratio: 21

44% 82% are T cells 59% of CD4 T cells (44% of lymphocytes) are negative for both CD7 and CD26 CD4:CD8 ratio: 8.5

– Reversed CD4/CD8 ratio of 0.24 observed

8% 49% T cells 84% of CD4+ T cells are CD26–, CD7–, CD30+ CD4:CD8 ratio: 1.3

TCR β, δ, and γ clonality

TCR β and γ clonality

TCR β clonality

Clonality not detected

Skin biopsy not diagnostic of MF

Skin biopsy diagnostic of CTCL

Skin biopsy diagnostic of CTCL

Laboratory findings LDH High HTVL-1 Negative Blood involvement Sézary count 80% Flow cytometry 85% T cells 80% CD7/CD26– CD4:CD8 ratio: >10

TCR clonality analysis Blood TCR β clonality Skin biopsy

Diagnostic of MF / Sézary syndrome with CD30+ cells

Skin biopsy initially not diagnostic of MF

Imaging studies

Extensive disease

Bilateral, enlarged, No lymphadenopathy inguinal, and axillary or visceral disease lymph nodes on CT thorax, abdomen, and pelvis

No lymphadenopathy or visceral disease

–

Treatments

Topical steroids; antibiotics; isotretinoin; IFN-α; ECP; brentuximab vedotin

Topical steroids; NBUVB; PUVA; alitretinoin; IFN-α

Topical steroids; NBUVB; isotretinoin; IFN-α

Topical steroids; NBUVB; alitretinoin

Topical steroids; NBUVB; alitretinoin

Diagnosis

Sézary syndrome

Leukemic CTCL

Leukemic CTCL

MF with evidence of blood clonality

Leukemic CTCL

Clinical disease outcome

Rapidly progressing, T1a to stage IVA disease in months with lymph-node and high blood tumor burden He was started on IFN-α, ECP, and isotretinoin Patient then developed skin tumors (large-cell transformation) at which point ECP was stopped and brentuximab vedotin was started

Indolent stage IB patch MF for 4 years, progressed to stage IVA leukemic CTCL with lymph-node involvement as confirmed by a CT scan Patient is stable on a multimodality treatment

Patient with a 2-year history of nonresolving eruption on the trunk that spared skin folds Patient was found to have a leukemic CTCL and was started on multimodality treatment

Patient with a 5-year history of itchy rash on the trunk that did not respond to topical steroids and was sparing skin folds Patient was found to have T-cell clonality in the blood and was started on alitretinoin in addition to skin-directed therapy

Indolent stage IB patch/plaque MF for 6 years, progressed to leukemic CTCL with a high proportion of CD30+ T cells in the blood

BSA, body surface area; CTCL, cutaneous T-cell lymphoma; LDH, lactate dehydrogenase; HTVL-1, human T-lymphotropic virus-1; CD, cluster designation; TCR, T-cell rearrangement gene study; NBUVB, narrow-band ultraviolet B phototherapy; PUVA, psoralen with ultraviolet A phototherapy; MF, mycosis fungoides; ECP, extracorporeal photophoresis.




Table 2. Proposed work-up to confirm or exclude a “deck-chair sign” or papuloerythroderma of Ofuji-like

cutaneous T-cell lymphoma (CTCL) based on present study findings and recent review [15] History and physical examination Age Sex Ethnicity and geographic place of origin History of presenting illness Onset and progression Previous and current treatments Past medical history Family history Cutaneous involvement Patch, plaque, tumor Alopecia (folliculotropic presentation) Presence of ectropion Deck-chair-sign skin eruption Body surface area involvement based on the modified severity-weighted assessment tool (mSWAT) Systemic involvement Palpable lymph node(s) Hepatosplenomegaly Skin biopsy Histopathological examination of skin biopsy consistent with CTCL Blood involvement Flow cytometry B1 Sézary cell count (>5%) B2 Sézary cell count (≥1,000 cells/μL) with a positive clone or Increased CD4+ or CD3+ cells with a CD4:CD8 ratio of ≥10 or Increased CD4+ cells and CD4+CD7– cells ≥40% or Increased CD4+ cells and CD4+CD26– ≥30% T-Cell Clonality T-cell rearrangement in blood and skin (PCR analysis) Other LDH (blood) HTLV-1 status (serology) Immunophenotype analysis (skin biopsy) Presence of large-cell transformation (skin biopsy) CD30+ positivity (skin biopsy and flow cytometry analysis) PCR, polymerase chain reaction; LDH, lactate dehydrogenase; HTLV-1, human T-lymphotropic virus-1.

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